Long acting opioid antagonists

ABSTRACT

Sustained release formulations of opioid antagonists containing both free and encapsulated opioid antagonist are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 62/721,204 filed Aug. 22, 2018, entitled “ExtendedRelease Naloxone for Sustained Acute Opioid Overdose Reversal” and U.S.Provisional Application No. 62/610,998 filed Dec. 28, 2017 entitled“Extended Release Naloxone for Sustained Acute Opioid OverdoseReversal”, the disclosures of which are incorporated herein by referencein their entireties.

GOVERNMENT INTERESTS

Not applicable

PARTIES TO A JOINT RESEARCH AGREEMENT

Not applicable

INCORPORATION OF MATERIAL ON COMPACT DISC

Not applicable

BACKGROUND

The proliferation of synthetic opioid availability and abuse,particularly the highly potent mu opioid receptor (MOR) agonist fentanyland related analogues (10-1000 times more lethal than heroin), has ledto an unprecedented rise in opioid overdoses and deaths in the UnitedStates. Because these drugs are readily absorbed via transdermal, andinhalation routes, there is an increasing direct threat to firstresponders and law enforcement for accidental overdose level exposure.The primary means of reversing an opioid overdose is the administrationof a MOR antagonist, such as naloxone. However, the current generationof MOR antagonists on the market do not have the required properties totreat a fentanyl overdose.

Fentanyl is a small hydrophobic molecule that activates the MOR at anEC50 of ˜1 nM. Naloxone is hydrophilic and requires 50-fold higherconcentration to antagonize MOR. Fentanyl and related analogues'hydrophobicity “protect” these compounds from metabolic degradation dueto sequestration in adipose tissue (half-life ˜7-10 hrs.), whilenaloxone exhibits poor tissue uptake and has a very transient half-life(˜1 hr.) due to rapid metabolic clearance. Taken together, this leads toa phenomenon known as “renarcotization” in which a patient treated withnaloxone can overdose from residual fentanyl leaching from adiposetissue. As a result, there is a critical need to create new formulationsof MOR antagonists that can combat a fentanyl overdose and provide themulti-hour antagonist activity required for safe and complete fentanylclearance from circulation.

To date, the development of new and more effective MOR antagonists hasbeen very limited. This is a direct result of the chemical compositionthis family of compounds share. Naloxone and other MOR antagonistsundergo rapid excretion from the body because 1) their relativehydrophilicity precludes absorption by circulatory proteins or adiposetissue and 2) the metabolically labile 3′ phenolic moiety that israpidly metabolized by the UDP-Glucuronosyltransferase-2B7 enzyme toform Naloxone-3-glucuronide. This phenolic moiety is present in allcurrently available opioid antagonists (e.g., naloxone, naltrexone, andNalmefene) and is crucial for their bioactivity. Nalmefene, a derivativeof naltrexone used primarily in management of alcohol dependence(outside the US) and previously as an emergency opioid overdose antidote(REVEX™, discontinued in 2008), achieved the longest half-life of anyantagonist developed to date. In a study comparing the ability ofnaloxone and nalmefene to reverse respiratory depression induced byfentanyl infusion in healthy adult volunteers, naloxone and nalmefeneexhibited identical potency at the same dose, while the duration ofaction was about twice as long with nalmefene (108 vs. 55 min) (Glass etal. Anesth Analg. 1994 March; 78(3):536-41). Though significant, thisincrease in duration of action to antagonize fentanyl is not sufficientto remove renarcotization potential in an overdose situation.

Embodiments of the invention directly address this immediate need in thecurrent opioid epidemic. The compositions described herein can be usedto deliver naloxone as an injectable in-situ drug depot for extendedrelease emergency treatment of opioid overdose by providing therapeuticplasma levels directly following injection and for a predetermined timeinterval thereafter. Specifically, the invention covers thereformulation of naloxone into a long acting injectable (LAI) that canprovide sustained antagonist activity in vivo. The reformulationcomposition will be the first reformulation effort aimed atsignificantly increasing naloxone duration of action (12+ hrs.) withoutchemical modifications, but instead by utilizing provenmicroencapsulation and extended release technologies. The formulationsof various embodiments contain both free naloxone andmicroencapsulated/extended release naloxone to provide immediate andsustained antagonist activity. This innovative design ensures that theformulations described herein will be able to combat both primary andsecondary overdose (renarcotization) situations.

SUMMARY OF THE INVENTION

Various embodiments are directed to compositions containing free opioidantagonist and microparticles of encapsulated opioid antagonist. In someembodiments, the compositions may have a ratio of free opioid antagonistto encapsulated opioid antagonist of about 1:10 to about 1:50.

In certain embodiments, the free opioid antagonist may be about 0.4milligrams (mg) to about 4 mg of opioid antagonist. The free opioidantagonist of various embodiments may be naloxone(17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt,or hydrate form, naltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form,nalmefene (6-desoxy-6-methylenenaltrexone) in free base, salt, orhydrate form, or any combination thereof.

In some embodiments, the encapsulated opioid antagonist may be about 10mg to about 30 mg of encapsulated opioid antagonist. The encapsulatedopioid antagonist of various embodiments may be naloxone(17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt,or hydrate form, naltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form,nalmefene (6-desoxy-6-methylenenaltrexone) in free base, salt, orhydrate form, or any combination thereof.

The microparticles may have a mean particle diameter of about 40 μm toabout 60 μm, and in some embodiments, the microparticles may be composedof a biodegradable polymer such as PLGA, PLA, PGA, PBS, PHA, PCL, PHB,PHV, PHBV, PEG, PLEG, and copolymers thereof, or combinations thereof.In certain embodiments, the PLGA may be capped. In some embodiments, thePLGA may have a ratio of PLA to PGA of 50:50 by weight to about 60:40 byweight. In particular embodiments, the biodegradable polymer may includepolymer units having molecular weights of about 5 kiloDalton (kDa) toabout 150 kDa. In some embodiments, the opioid antagonist loading may beabout 0.5 wt. % to about 50 wt. %.

Other embodiments are directed to a method for treating or preventingopioid overdose including the steps of administering to a subject inneed of treatment a composition comprising free opioid antagonist andmicroparticles of encapsulated opioid antagonist. In some embodiments,the compositions may have a ratio of free opioid antagonist toencapsulated opioid antagonist of about 1:10 to about 1:50.

In certain embodiments, the free opioid antagonist may be about 0.4milligrams (mg) to about 4 mg of opioid antagonist. The free opioidantagonist of various embodiments may be naloxone(17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt,or hydrate form, naltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form,nalmefene (6-desoxy-6-methylenenaltrexone) in free base, salt, orhydrate form, or any combination thereof.

In some embodiments, the encapsulated opioid antagonist may be about 10mg to about 30 mg of encapsulated opioid antagonist. The encapsulatedopioid antagonist of various embodiments may be naloxone(17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt,or hydrate form, naltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form,nalmefene (6-desoxy-6-methylenenaltrexone) in free base, salt, orhydrate form, or any combination thereof.

The microparticles may have a mean particle diameter of about 40 μm toabout 60 μm, and in some embodiments, the microparticles may be composedof a biodegradable polymer such as PLGA, PLA, PGA, PBS, PHA, PCL, PHB,PHV, PHBV, PEG, PLEG, and copolymers thereof, or combinations thereof.In certain embodiments, the PLGA may be capped. In some embodiments, thePLGA may have a ratio of PLA to PGA of 50:50 by weight to about 60:40 byweight. In particular embodiments, the biodegradable polymer may includepolymer units having molecular weights of about 5 kiloDalton (kDa) toabout 150 kDa. In some embodiments, the opioid antagonist loading may beabout 0.5 wt. % to about 50 wt. %.

In particular embodiments, administration may result in a plasmaconcentration in the subject of greater than about 2 ng/ml for up toabout 7 days, and in various embodiments, administration may be carriedout by depo injection, intramuscular injection, subcutaneous injection,oral, sublingual, and intranasal administration.

DESCRIPTION OF THE DRAWINGS

For a fuller understanding of the nature and advantages of theinvention, reference should be made to the following detaileddescription taken in connection with the accompanying drawings, inwhich:

FIG. 1 is a diagram showing the process for making encapsulatednaloxone. 2

FIG. 2 is a graph showing simulated release of naloxone formulated tocontain both free naloxone and microparticle-encapsulated naloxone (reddotted line above) that achieves immediate and sustained MOR antagonistactivity in vivo. Such a formulation provides relief from primary andpotential secondary overdose events.

DETAILED DESCRIPTION

Various aspects now will be described more fully hereinafter. Suchaspects may, however, be embodied in many different forms and should notbe construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey its scope to those skilled in theart.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 μm to 8μm is stated, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are also intendedto be explicitly disclosed, as well as the range of values greater thanor equal to 1 μm and the range of values less than or equal to 8 μm andnon-integers such as 2.5 μm, 4.33 μm, 5.25 μm, 6.75 μm, and the like.

All percentages, parts and ratios are based upon the total weight of thetopical compositions and all measurements made are at about 25° C.,unless otherwise specified.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference toa “polymer” includes a single polymer as well as two or more of the sameor different polymers; reference to an “excipient” includes a singleexcipient as well as two or more of the same or different excipients,and the like.

The word “about” when immediately preceding a numerical value means arange of plus or minus 10% of that value, e.g, “about 50” means 45 to55, “about 25,000” means 22,500 to 27,500, etc, unless the context ofthe disclosure indicates otherwise, or is inconsistent with such aninterpretation. For example, in a list of numerical values such as“about 49, about 50, about 55, “about 50” means a range extending toless than half the interval(s) between the preceding and subsequentvalues, e.g, more than 49.5 to less than 52.5. Furthermore, the phrases“less than about” a value or “greater than about” a value should beunderstood in view of the definition of the term “about” providedherein.

The terms “administer,” “administering,” or “administration” as usedherein refer to either directly administering a compound (also referredto as an agent of interest) or pharmaceutically acceptable salt of thecompound (agent of interest) or a composition to a subject.

The term “carrier” as used herein encompasses carriers, excipients, anddiluents, meaning a material, composition or vehicle, such as a liquidor solid filler, diluent, excipient, solvent or encapsulating materialinvolved in carrying or transporting a pharmaceutical, cosmetic or otheragent across a tissue layer such as the stratum corneum or stratumspinosum.

The terms “effective amount” and “therapeutically effective amount” areused interchangeably in this disclosure and refer to an amount of acompound that, when administered to a subject, is capable of reducing asymptom of a disorder in a subject or enhance the texture, appearance,color, sensation, or hydration of the intended tissue treatment area.The actual amount which comprises the “effective amount” or“therapeutically effective amount” will vary depending on a number ofconditions including, but not limited to, the severity of the disorder,the size and health of the patient, and the route of administration. Askilled medical practitioner can readily determine the appropriateamount using methods known in the medical arts.

The phrase “pharmaceutically acceptable” or “cosmetically acceptable” isemployed herein to refer to those agents of interest/compounds, salts,compositions, dosage forms, etc, which are—within the scope of soundmedical judgment—suitable for use in contact with the tissues of humanbeings and/or other mammals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio. In some aspects, pharmaceuticallyacceptable means approved by a regulatory agency of the federal or astate government, or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in mammals (e.g., animals), and moreparticularly, in humans.

The term “salts” as used herein embraces pharmaceutically acceptablesalts commonly used to form alkali metal salts of free acids and to formaddition salts of free bases. The nature of the salt is not critical,provided that it is pharmaceutically acceptable. The term “salts” alsoincludes solvates of addition salts, such as hydrates, as well aspolymorphs of addition salts. Suitable pharmaceutically acceptable acidaddition salts can be prepared from an inorganic acid or from an organicacid. Non-limiting examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoricacid. Appropriate organic acids can be selected from aliphatic,cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containingcarboxylic acids and sulfonic acids, for example formic, acetic,propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic,glutamic, benzoic, anthranilic, mesylic, stearic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric andgalacturonic acid.

The term “patient” and “subject” are interchangeable and may be taken tomean any living organism which may be treated with compounds of thepresent invention. As such, the terms “patient” and “subject” mayinclude, but is not limited to, any non-human mammal, primate or human.In some embodiments, the “patient” or “subject” is a mammal, such asmice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, primates, or humans. In some embodiments, the patient or subjectis an adult, child or infant. In some embodiments, the patient orsubject is a human.

The term “prevent” as used herein shall mean stopping or reducing theseverity of symptoms related to opioid ingestion or overdose.

The term “treating” is used herein, for instance, in reference tomethods of treating a skin disorder or a systemic condition, andgenerally includes the administration of a compound or composition whichreduces the frequency of, or delays the onset of, symptoms of a medicalcondition or enhance the texture, appearance, color, sensation, orhydration of the intended tissue treatment area of the tissue surface ina subject relative to a subject not receiving the compound orcomposition. This can include reversing, reducing, or arresting thesymptoms, clinical signs, and underlying pathology of a condition in amanner to improve or stabilize a subject's condition.

By hereby reserving the right to proviso out or exclude any individualmembers of any such group, including any sub-ranges or combinations ofsub-ranges within the group, that can be claimed according to a range orin any similar manner, less than the full measure of this disclosure canbe claimed for any reason. Further, by hereby reserving the right toproviso out or exclude any individual substituents, analogs, compounds,ligands, structures, or groups thereof, or any members of a claimedgroup, less than the full measure of this disclosure can be claimed forany reason. Throughout this disclosure, various patents, patentapplications and publications are referenced. The disclosures of thesepatents, patent applications and publications in their entireties areincorporated into this disclosure by reference in order to more fullydescribe the state of the art as known to those skilled therein as ofthe date of this disclosure. This disclosure will govern in the instancethat there is any inconsistency between the patents, patent applicationsand publications cited and this disclosure.

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to 5 which thisdisclosure belongs.

Various embodiments of the invention are directed to pharmaceuticalcompositions for sustained release of opioid antagonists such as, forexample, naloxone, naltrexone, or nalmefene, over a period of up toabout 7 days and, in some embodiments, about 10 hours to about 7 days orabout 12 hours to about 7 days, about 10 hours to about 7 days, about 12hours to about 5 days, about 10 hours to about 4 days, about 12 hours toabout 4 days, about 10 hours to about 72 hours, about 12 hours to about48 hours, or any range or individual time encompassed by these examples.Such compositions may contain a mixture of free opioid antagonists andencapsulated opioid antagonists such that a plasma concentration ofgreater than about 2 ng/ml of opioid antagonist is maintained for up toabout 7 days, up to about 5 days, up to about 4 days, up to about 72hours, about 1 hour to about 24 hours, about 2 hours to about 24 hours,about 5 hours to about 24 hours, about 2 hours to about 12 hours, about5 to about 12 hours, about 5 to about 24 hours, about 5 hours to about48 hours, about 5 hours to about 36 hours. For example, the plasmaconcentration may be about 2 ng/ml to about 10 ng/ml, about 2 ng/ml toabout 8 ng/ml, about 2 ng/ml to about 5 ng/ml, or any plasmaconcentration or range encompassed by these example ranges. Inparticular embodiments, the formulation may include about 0.4 to about 4mg of free opioid antagonists and about 10 mg to about 30 mg ofencapsulated opioid antagonists. Further embodiments are directed tomethods for treating opioid overdose by administering to a patient inneed of treatment a formulation of opioid antagonists containing freeopioid antagonists and encapsulated opioid antagonists.

The term “free opioid antagonists” refers to opioid antagonists in freebase, salt, or hydrate form that is not encapsulated nor covalentlyassociated with an excipient. For example, “free opioid antagonists” canrefer to naloxone (17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) infree base, salt, or hydrate form (e.g. naloxone, naloxone HCl(“Narcan”), naloxone HCl dehydrate, or other naloxone salts) ornaltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) that is not encapsulated in a microparticleor nanoparticle.

The term “encapsulated opioid antagonist” refers to opioid antagonist,in free base, salt, or hydrate form, that is encapsulated in amicroparticle or nanoparticle. Embodiments are not limited to particulartypes of microparticles or nanoparticles. For example, in certainembodiments, an active agent may be encapsulated in microparticles madefrom biodegradable polymers, such as polylactides (PLA), poly glycolides(PGA), and poly(lactide-co-glycolide) (PLGA) polymers. In someembodiments, the microparticles may also include derivatives of PLA orPGA, such as poly butylene succinate (PBS), polyhydroxyalkanoate (PHA),polycaprolactone acid lactone (PCL), polyhydroxybutyrate (PHB), glycolicamyl (PHV), PHB and PHV copolymer (PHBV), and poly lactic acid(PLA)-polyethylene glycol (PEG) copolymers (PLEG). PLA/PGA/PLGA degradein the body by simple hydrolysis of the ester backbone to non-harmfuland non-toxic compounds. The in vivo degradation products are eitherexcreted by the kidneys or eliminated as carbon dioxide and waterthrough well-known biochemical pathways. Typically, the active agent canbe entrapped in solid microparticles in which release of the agent isachieved by either bioerosion of the microparticles or diffusion out ofthe microparticle.

For purposes of this disclosure reference to a single biodegradable ismeant to encompass the other biodegradable polymers. For example, theterm “PLGA microparticle” as used herein below is meant as examplebiodegradable polymer, and is meant to encompass microparticle composedof PLGA as well as microparticles composed of PLA, PGA, PBS, PHA, PCL,PHB, PHV, PHBV, PEG, PLEG, and copolymers thereof.

The molecular weight of the biodegradable polymer units that make up themicroparticles can affect the rate of degradation of the microparticleand subsequent release of the drug. For example, microparticles composedof polymer units having low molecular weights generally degrade fasterand release the drug at an earlier period when compared tomicroparticles composed of polymer with high molecular weight polymerunits. In various embodiments, the microparticles may be composed ofpolymer units having molecular weights of from about 5 kiloDalton (kDa)to about 150 kDa, about 5 kDa to about 125 kDa, about 10 kDa to about100 kDa, about 15 kDa to about 75 kDa, or about 20 kDa to about 50 kDa,or any individual molecular weight or range encompassed by these exampleranges. Specific examples include about 5 kDa, about 10 kDa, about 15kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 40 kDa, about 50kDa, about 60 kDa, about 75 kDa, about 100 kDa, about 150 kDa, andranges between any of these example values.

In some embodiments, the ratio of biodegradable polymer components, forexample, PLA to PGA, in the microparticles can be about 1:99 to about99:1 by weight, about 10:90 to about 90:10 by weight, about 30:70 toabout 70:30 by weight, about 40:60 to about 60:40 by weight, about 50:50by weight, or about 30:70 to about 40:60 by weight. Specific examples ofratio of PLA to PGA include about 30:70 by weight, about 40:60 byweight, 50:50 by weight, about 60:40 by weight, about 70:30 by weight,about 75:25 by weight, and ranges between any two of these values.Microparticles having a higher concentration of lactide units degrademore slowly allowing for delayed release of the active agent.

Microparticles of encapsulated opioid antagonist can have a meanparticle diameter (MPD) of about 0.5 micrometers (μm) to about 90 μm,about 1 μm to about 75 μm, about 2 μm to about 70 μm or any range orindividual value encompassed by these example ranges. In particular 7embodiments, the mean particle diameter of the microparticles may beabout 30 μm to about 70 μm, about 35 μm to about 65 μm, about 40 μm toabout 60 μm, or any individual diameter or range encompassing theseexample ranges. In various embodiments, the microparticles may have amonomodal particle size distribution in which a single maximumdiscernable on a particle size distribution curve (weight percent orpopulation on the ordinate or Y-axis, and particle size/diameter on theabscissa or X-axis). In some embodiments, the microparticles may have amonodisperse particle size distribution, meaning all of the particleshave substantially the same mass.

In various embodiments, the microparticles may have an opioid antagonistloading of about 0.5 wt. % to about 50 wt. %, about 1 wt. % to about 40wt. %, about 10 wt. % to about 35 wt. %, about 15 wt. % to about 25 wt.%, or any range or individual value encompassed by these ranges. “Drug(e.g., opioid antagonist) loading” as used herein is defined as theweight of drug in the final microparticle formulation divided by theweight of microparticles in the final formulation (units of % w/w; e.g.weight naloxone/weight PLGA).

The biodegradable polymer components of the microparticles, for example,PLGA, may be capped or uncapped. The term “uncapped PLGA” indicates thatthe PLGA of the microparticles described or its underlying components,PLA and PGA, have not been functionalized. Thus, “uncapped PLGA” or“uncapped microparticles” contain carboxyl (—COOH) end groups at polymercomponent termini. The term “capped PLGA” or “capped microparticles”indicates that the PLGA of the microparticles described or itsunderlying components, PLA and PGA, have been functionalized. Forexample, the carboxyl end groups of “capped PLGA” have undergone achemical reaction, i.e. functionalization, to produce, for example,ester end groups (—COOR). Without wishing to be bound by theory, cappedPLGA may be less charged and, therefore, less likely to produce ionicinteractions with free opioid antagonists. The use of capped PLGA inmicroparticles may reduce or eliminate any delay in immediate release ofopioid antagonist upon administration of the formulations of embodimentsof the invention.

The microparticle encapsulation of opioid antagonists can be performedby any means. For example, as illustrated in FIG. 1, PLGA polymers ofknown molecular weights can be dissolved in organic solvents, such ashalogenated hydrocarbons such as methylene chloride, chloroform, andcarbon tetrachloride; aromatic hydrocarbons such as toluene and xylene;or mixtures or combinations thereof. The opioid antagonists may bedissolved in an aqueous solvent, such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose, lecithin, and gelatin, and thePLGA solution and the anticancer agent solution can be mixed andsonicated to form a uniform distribution of the opioid antagonists andthe PLGA polymer. Homogenization is subsequently performed to form thepolymer particle emulsion. The resulting polymer emulsion is stirreduntil the organic solvent is evaporated, resulting in precipitation ofpolymer particles that encapsulate the opioid antagonists. The size ofthe microparticles may be controlled by varying homogenization speedduring emulsification.

The ratio of free opioid antagonist to encapsulated antagonist in theformulations of embodiments, may range from about 100:1 to about 1:100,and in certain embodiments, the ratio of free opioid antagonist toencapsulated antagonist may be about 1:1 to about 1:80, about 1:5 toabout 1:60, about 1:10 to about 1:50, or any range or individual ratioencompassed by these example ranges. In some embodiments, theformulation may include about 0.4 to about 4 mg of free opioidantagonists and about 10 mg to about 30 mg of encapsulated opioidantagonists. Thus, microparticles may make up about 50 wt. % to about 95wt. % of the formulation, or about 60 wt. % to about 90 wt. %, about 75wt. % to about 90 wt. % of the total formulation or any range orindividual value encompassed by these example ranges.

The pharmaceutical compositions disclosed herein provide for sustainedrelease of opioid antagonist for a time period of about 12 hours toabout 36 hours or about 48 hours. “Sustained release” refers to theprocess in which the opioid antagonist is released gradually over aperiod of time. As illustrated in FIG. 2, In the context of theformulations of the invention, free opioid antagonist may provide aninitial burst of opioid antagonist released immediately up onadministration of the formulation. The microparticles or nanoparticlesmay allow for sustained release of opioid antagonist after the initialburst has dissipated and/or the effect of the opioid antagonist has wornoff. Thus, the formulations of embodiments may provide an initial doseof opioid antagonist that is sufficient to reverse an opioid overdose.Release of opioid antagonist from the microparticles in the formulationmay continue to block opioid receptors as residual opioid, e.g.,fentanyl, is leached from adipose tissue reducing the likelihood ofrenarcotization.

Further embodiments include compositions containing opioid antagonistsdissolved in oils producing a sustained release formulation. In suchembodiments, the opioid antagonists may ionically associate with theoils without forming microparticles or nanoparticles. Without wishing tobe bound by theory, this ionic association may delay release of theopioid antagonist after administration as the oil is broken downreleasing additional opioid antagonist over time. The oil used in suchembodiments is not limited, for example, the oil may be vegetable oil,olive oil, grapeseed oil, tea tree oil, almond oil, avocado oil, sesameoil, evening primrose oil, sunflower oil, kukui nut oil, jojoba oil,walnut oil, peanut oil, pecan oil, macadamia nut oil, coconut oil, andthe like and combinations thereof. The amount of opioid antagonist insuch embodiments may be from about 2 mg to about 30 mg, or any range orindividual amount encompassed by this range, and the oil may make up theremaining volume of the composition. In some embodiments, the opioidantagonist may be a free base form of the opioid antagonist, forexample, naloxone free base or naltrexone free base, which may renderthe opioid antagonist more hydrophobic and more soluble in the oil thansalt forms of the opioid antagonists.

The sustained release pharmaceutical compositions disclosed herein mayfurther contain a hydrogel. The hydrogel may help to hold themicroparticles in the composition without clumping, maintain theintegrity of the microparticles by buffering the pH, and aid inadministration of the composition. Non-limiting examples of hydrogelsinclude methyl cellulose (MC), ethyl cellulose (EC), ethyl methylcellulose (EMC), hydroxyethyl cellulose (HEC), hydroxylpropyl cellulose(HPC), hydroxymethyl cellulose (HMC), hydroxypropylmethyl cellulose(HPMC), ethylhydroxyethyl cellulose (EHEC), hydroxyethylmethy cellulose(HEMC), methylhydroxyethyl cellulose (MHEC),methylhydroxypropylcellulose (MHPC), and hydroxyethylcarboxymethylcellulose (HECMC).

Other materials that can be used to form a hydrogel include modifiedalginates. Alginate is a carbohydrate polymer isolated from seaweed thatcan be crosslinked to form a hydrogel by exposure to a divalent cation,such as calcium. Additionally, polysaccharides that gel by exposure tomonovalent cations, including bacterial polysaccharides, such as gellangum, and plant polysaccharides, such as carrageenans, may be crosslinkedto form a hydrogel, using methods known in the art. Tragacanth, pectin,guar gum, xanthan gum, and polyacrylamide may also be used as hydrogels.

In some embodiments, the formulations discussed above may have aninherent viscosity of about 300 cP or less, about 200 cP or less, about100 cP or less or about 50 cP or less. Combinations of viscosityreducing agents may be used to achieve the desired viscosity. Forexample, polyethylene glycol polymers, surfactants, organic solvents,aqueous solvents and combinations thereof are suitable for use asviscosity reducing agents. The amount of viscosity reducing agentpresent in the sustained release composition can range from about 5 wt %to about 40 wt % of the total weight of the sustained releasecomposition.

The pharmaceutical compositions of the invention are typically used inthe form of a drug reservoir such as injectable microparticles, passivetransdermal/transmucosal drug delivery or electrotransport drug deliverysystems. It will be appreciated by those skilled in the art that theinventive formulations described herein can be combined with suitablecarriers to prepare alternative drug dosage forms (e.g., oral capsule,topical ointment, rectal and/or vaginal suppositories, buccal patches,or an aerosol spray).

It is also known in the art that the active ingredients can be containedin such formulations with pharmaceutically acceptable diluents, fillers,disintegrants, binders, lubricants, surfactants, hydrophobic vehicles,water soluble vehicles, emulsifiers, buffers, humectants, moisturizers,solubilizers, preservatives and the like. The means and methods foradministration are known in the art and an artisan can refer to variouspharmacologic references for guidance. For example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman& Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co., New York (1980) can be consulted.

Pharmaceutical compositions disclosed herein can include suitable solidor gel phase carriers or excipients. Examples of such carriers orexcipients include but are not limited to calcium carbonate, calciumphosphate, various sugars, starches, cellulose derivatives, gelatin, andpolymers such as, e.g., polyethylene glycols. In some embodiments, thepharmaceutical excipient may include, without limitation, binders,coating, disintegrants, fillers, diluents, flavors, colors, lubricants,glidants, preservatives, sorbents, sweeteners, conjugated linoleic acid(CLA), gelatin, beeswax, purified water, glycerol, any type of oil,including, without limitation, fish oil or soybean oil, or the like.

In some embodiments, the pharmaceutical composition may include one ormore disintegrant component, such as croscarmellose sodium, carmellosecalcium, crospovidone, alginic acid, sodium alginate, potassiumalginate, calcium alginate, an ion exchange resin, an effervescentsystem based on food acids and an alkaline carbonate component, clay,talc, starch, pregelatinized starch, sodium starch glycolate, cellulosefloc, carboxymethylcellulose, hydroxypropylcellulose, calcium silicate,a metal carbonate, sodium bicarbonate, calcium citrate, or calciumphosphate.

In some embodiments, the pharmaceutical composition may include one ormore diluent component, such as mannitol, lactose, sucrose,maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystallinecellulose, carboxymethyl-cellulose, carboxyethylcellulose,methylcellulose, ethylcellulose, hydroxyethylcellulose,methylhydroxyethylcellulose, starch, sodium starch glycolate,pregelatinized starch, a calcium phosphate, a metal carbonate, a metaloxide, or a metal aluminosilicate.

In some embodiments, the pharmaceutical composition may include one ormore optional lubricant component, such as stearic acid, metallicstearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acidester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine,silica, silicic acid, talc, propylene glycol fatty acid ester,polyethoxylated castor oil, polyethylene glycol, polypropylene glycol,polyalkylene glycol, polyoxyethylene-glycerol fatty ester,polyoxyethylene fatty alcohol ether, polyethoxylated sterol,polyethoxylated castor oil, polyethoxylated vegetable oil, or sodiumchloride.

Disclosed herein are methods for treating opioid overdose in a subject.In various embodiments, such methods may include the step ofadministering a therapeutically effective amount of a formulationdisclosed herein. In various embodiments, the subject may beexperiencing opioid overdose or symptoms related thereto, such as, forexample, vomiting, dilated pupils, extreme sleepiness, or the inabilityto wake up, intermittent loss of consciousness, slowed or irregularbreathing, respiratory arrest (absence of breathing), cold, clammy skin,or bluish skin around the lips or under the fingernails, and the likeand combinations thereof.

The term “subject” includes animals which can be treated using themethods of the invention. Examples of animals include mammals, such asmice, rabbits, rats, horses, goats, dogs, cats, pigs, cattle, sheep, andprimates (e.g. chimpanzees, gorillas, and humans).

Certain embodiments are directed to veterinary formulations and methodsfor administration of the compositions of the invention to animals suchas dogs, cats, pigs, and horses. Animals trained for use in lawenforcement, particularly “drug detection dogs,” are often used to findillicit drugs including opioids. As such, these animals inadvertentlyinhale amounts of opioids sufficient to cause overdose. Thus,embodiments are directed to veterinary compositions, as described above,for sustained release of opioid antagonists such as, for example,naloxone, naltrexone, or nalmefene, over a period of up to about 7 days,and in some embodiments, up to about 12 or up to about 24 hours. Suchcompositions can be administered by any means described below eitherprophylactically, i.e. before the animal is exposed to, or potentialexposed to opioids, mitigate the effects of opioids on the animal orafter the animal is exposed to opioids to limit adverse effects of theexposure.

Administration of any of the compositions described above eitherformulated for humans or animals can be systemic, parenteral,intranasal, topical, or oral. For example, administration can be, but isnot limited to, parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, oral, buccal, ocular routes, orintravaginally, by inhalation, by depot injections, or by implants. Inparticular embodiments, administering can be carried out by injectionincluding, for example, depot injection, intramuscular injection, orsubcutaneous injection, and the like, or by oral, sublingual, orintranasal administration, and the like. The selection of the specificroute of administration and the dose regimen is to be adjusted ortitrated by the clinician according to methods known to the clinician inorder to obtain the optimal clinical response. The amount of compoundsto be administered is that amount which is therapeutically effective.The dosage to be administered will depend on the characteristics of thesubject being treated, e.g., the particular animal or human beingtreated, age, weight, health, types of concurrent treatment, if any, andfrequency of treatments, and can be easily determined by one of skill inthe art (e.g., by the clinician). Administration can be carried out by aclinician, or in other embodiments can be carried out by a firstresponder, emergency medical technician (EMT), bystander, friend, orfamily member with access to the compositions of embodiments in adeliverable form, for example, a prefilled syringe or kit.

In certain embodiments, the formulations of embodiments may beadministered by a syringe. The sustained release composition isformulated so that the composition can be readily implanted (e.g., byinjection) into the desired location to form a mass that can remain inplace for the period suitable for controlled release of the opioidantagonist. The mechanical and rheological properties suitable forinjectable depot compositions are known in the art. Typically, thepolymer of the depot vehicle with particulates are present in anappropriate amount of solvent such that the depot composition can be soimplanted.

For oral administration, the pharmaceutical composition can beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions and the like, for oral ingestion by a patient tobe treated. Pharmaceutical preparations for oral use can be obtained byadding a solid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipientsinclude, but are not limited to, fillers such as sugars, including, butnot limited to, lactose, sucrose, mannitol, and sorbitol; cellulosepreparations such as, but not limited to, maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, andpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as, but not limited to, the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

For oral administration, the hydrogel formulation is preferablyencapsulated by a retardant coating, e.g., a bioerodible polymer. Upondissolution or erosion of the encapsulating material, the hydrogel corebecomes exposed and the drug contained within the gel can be releasedfor enteric adsorption. Bioerodible coating materials may be selectedfrom a variety of natural and synthetic polymers, depending on the agentto be coated and the desired release characteristics. Exemplary coatingmaterials include gelatins, carnauba wax, shellacs, ethylcellulose,cellulose acetate phthalate or cellulose acetate butyrate. Release ofthe agent is controlled by adjusting the thickness and dissolution rateof the polymeric coat.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active doses.

Pharmaceutical preparations which can be used orally include, but arenot limited to, push-fit capsules made of gelatin, as well as soft,sealed capsules made of gelatin and a plasticizer, such as glycerol orsorbitol. The push-fit capsules can contain the active ingredients inadmixture with filler such as, e.g., lactose, binders such as, e.g.,starches, and/or lubricants such as, e.g., talc or magnesium stearateand, optionally, stabilizers. In soft capsules, the active compounds canbe dissolved or suspended in suitable liquids, such as fatty oils,liquid paraffin, or liquid polyethylene glycols. In addition,stabilizers can be added. All formulations for oral administrationshould be in dosages suitable for such administration.

For intranasal administration, the compositions for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitcan be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator can be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compositions of the present invention can also be formulated inrectal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

In transdermal administration, the compositions of the presentinvention, for example, can be applied to a plaster, or can be appliedby transdermal, therapeutic systems that are consequently supplied tothe organism. In some embodiments, the formulation can be deliveredusing microneedle apparatuses.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration.

The invention also provides kits for carrying out the therapeuticregimens of the invention. Such kits comprise in one or more containershaving therapeutically or prophylactically effective amounts of thesustained release compositions in pharmaceutically acceptable form. Thesustained release compositions in a vial of a kit of the invention maybe in the form of a pharmaceutically acceptable solution, e.g., incombination with sterile saline, dextrose solution, or bufferedsolution, or other pharmaceutically acceptable sterile fluid.Alternatively, the complex may be lyophilized or desiccated; in thisinstance, the kit optionally further comprises in a container apharmaceutically acceptable solution (e.g., saline, dextrose solution,etc.), preferably sterile, to reconstitute the complex to form asolution for injection purposes.

In another embodiment, a kit of the invention further comprises a needleor syringe, preferably packaged in sterile form, for injecting thecomplex, and/or a packaged alcohol pad. Instructions are optionallyincluded for administration of sustained release compositions by aclinician, first responder, emergency medical technician (EMT),bystander, friend, family member or the patient. Such kits may containone or more vials of a sustained release opioid antagonist formulationthat is manually loaded into a syringe before administering orautoinjectors that are pre-loaded with the formulation in an appropriateamount for administration.

EXAMPLES

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Therefore, the spirit and scope of the appended claimsshould not be limited to the description and the preferred versionscontained within this specification. Various aspects of the presentinvention will be illustrated with reference to the followingnon-limiting examples.

Example 1

A simulation was carried out for formulations containing 2 mg freenaloxone, 20 mg microencapsulated naloxone, and 2 mg free and 20 mgmicroencapsulated naloxone. Predicted PK data using human PK data fornaloxone HCl as a baseline is provided in FIG. 2. These data suggestthat a formulation that provides at least 2 ng/ml plasma concentrationof naloxone for a time period of at least 12 hours to 24 hours can beachieved by combining free naloxone and microencapsulated naloxone.

1. A composition comprising free opioid antagonist and microparticles of encapsulated opioid antagonist.
 2. The composition of claim 1, having a ratio of free opioid antagonist to encapsulated opioid antagonist of about 1:10 to about 1:50.
 3. The composition of claim 1, wherein the free opioid antagonist comprises about 0.4 milligrams (mg) to about 4 mg of opioid antagonist.
 4. The composition of claim 1, wherein the free opioid antagonist is selected from the groups consisting of naloxone (17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form, naltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3, 14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form, nalmefene (6-desoxy-6-methylenenaltrexone) in free base, salt, or hydrate form, and combinations thereof.
 5. The composition of claim 1, wherein the encapsulated opioid antagonist comprises about 10 mg to about 30 mg of encapsulated opioid antagonist.
 6. The composition of claim 1, wherein the encapsulated opioid antagonist is selected from the groups consisting of naloxone (17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form, naltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3, 14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form, nalmefene (6-desoxy-6-methylenenaltrexone) in free base, salt, or hydrate form, and combinations thereof.
 7. The composition of claim 1, wherein the microparticles have a mean particle diameter of about 40 μm to about 60 μm.
 8. The composition of claim 1, wherein the microparticles comprise a biodegradable polymer selected from the group consisting of PLGA, PLA, PGA, PBS, PHA, PCL, PHB, PHV, PHBV, PEG, PLEG, and copolymers thereof.
 9. The composition of claim 8, wherein the PLGA is capped.
 10. The composition of claim 8, wherein the PLGA comprises a ratio of PLA to PGA of 50:50 by weight to about 60:40 by weight.
 11. The composition of claim 8, wherein the biodegradable polymer comprises polymer units having molecular weights of about 5 kiloDalton (kDa) to about 150 kDa.
 12. The composition of claim 1, wherein opioid antagonist loading is about 0.5 wt. % to about 50 wt. %.
 13. A method for treating or preventing opioid overdose comprising administering to a subject in need of treatment a composition comprising free opioid antagonist and microparticles of encapsulated opioid antagonist.
 14. The method of claim 13, having a ratio of free opioid antagonist to encapsulated opioid antagonist of about 1:10 to about 1:50.
 15. The method of claim 13, wherein the free opioid antagonist comprises about 0.4 milligrams (mg) to about 4 mg of opioid antagonist.
 16. The method of claim 13, wherein the free opioid antagonist is selected from the groups consisting of naloxone (17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form, naltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3, 14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form, nalmefene (6-desoxy-6-methylenenaltrexone) in free base, salt, or hydrate form, and combinations thereof.
 17. The method of claim 13, wherein the encapsulated opioid antagonist comprises about 10 mg to about 30 mg of encapsulated opioid antagonist.
 18. The method of claim 13, wherein the encapsulated opioid antagonist is selected from the groups consisting of naloxone (17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form, naltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3, 14-dihydroxymorphinan-6-one) in free base, salt, or hydrate form, nalmefene (6-desoxy-6-methylenenaltrexone) in free base, salt, or hydrate form, and combinations thereof.
 19. The method of claim 13, wherein administration results in a plasma concentration in the subject of greater than about 2 ng/ml for up to about 7 days.
 20. The method of claim 13, wherein administration is selected from the group consisting of depo injection, intramuscular injection, subcutaneous injection, oral, sublingual, and intranasal administration. 